2-disubstituted cyclohexenyl and cyclohexyl antimicrobial agents
The invention relates to cyclohexenyl antibacterial compounds of the formula I: ##STR1## and pharmaceutical compositions containing the compounds, methods for their production and use.
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Claims
1. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound having activity as a histidine protein kinase inhibitor selected from those of the Formula I: ##STR71## wherein: R.sub.1 is selected from branched or unbranched (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, and a moiety of the formula: ##STR72## wherein: p is an integer from 0-6;
- and R.sub.3, R.sub.4 and R.sub.5 are independently selected from hydrogen, halo, (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy, hydroxy, hydroxyalkyl, amino, (C.sub.1 -C.sub.4) alkylamino, and nitro;
- n is an integer from 1-6;
- q is an integer from 0-2;
- X is selected from O and S;
- R.sub.2 is selected from phenyl and a heterocyclic moiety wherein the heterocyclic moiety is a monocyclic heterocyclic group having 5 or 6 ring atoms and 1-4 nitrogen, oxygen, or sulfur atoms and is saturated or unsaturated, and wherein the phenyl or heterocyclic moiety is substituted with amino, moieties of the formula: ##STR73## carboxy, carboxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylcarboxy, or a moiety of the formula: ##STR74## and, optionally, 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6) alkyl and (C.sub.1 -C.sub.6) alkoxy;
- wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl;
- R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6 ) alkyl, (C.sub.3 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, (C.sub.1 -C.sub.6)acyl, a moiety of the formula: ##STR75## and a moiety of the formula
- R.sub.8 is selected from amino, amino(C.sub.1 -C.sub.6)alkyl, amino((C.sub.1 -C.sub.6)alkyl).sub.2, an aryl group and a heterocyclic group wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 10 carbon atoms and the heterocyclic group is a monocyclic or bicyclic group of 4-10 ring atoms wherein the heteroatom or heteroatoms are selected from 1-4 oxygen, nitrogen or sulfur atoms and each ring of the heterocycle is composed of 4-6 atoms and is saturated or unsaturated; and the pharmaceutically acceptable salts thereof.
2. A method according to claim 1 wherein R.sub.1 is selected from branched or unbranched (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, and a moiety of the formula: ##STR76## wherein p is an integer from 0-6;
- and R.sub.3, R.sub.4 and R.sub.5 are independently selected from hydrogen, halo, (C.sub.1 -C.sub.4) alkyl, and (C.sub.1 -C.sub.4) alkoxy;
- n is an integer from 1-3;
- X is O or S;
- R.sub.2 is selected from phenyl, pyrimidine, pyrimidone and pyrazole and R.sub.2 is substituted with amino, moieties of the formula; ##STR77## carboxy, (C.sub.1 -C.sub.6)alkylcarboxy, carboxy(C.sub.1 -C.sub.6)alkyl, and a moiety of the formula: ##STR78## and, optionally 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6)alkyl, and (C.sub.1 -C.sub.6) alkoxy;
- wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl; and R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6) alkyl, (C.sub.4 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, a moiety of the formula: ##STR79## and a moiety of the formula:
- and the pharmaceutically acceptable salts thereof.
3. A compound of the Formula I: ##STR80## wherein: R1 is benzyl optionally substituted with one to three substituents independently selected from halo, (C.sub.1 -C.sub.4)alkyl, and (C.sub.1 -C.sub.4)alkoxy;
- n is an integer from 1-3;
- X is selected from O and S;
- q is an integer from 0-2;
- R.sub.2 is selected from phenyl, pyrimidine, pyrimidone and pyrazole and R.sub.2 is substituted with amino, moieties of the formula; ##STR81## carboxy, (C.sub.1 -C.sub.6)alkylcarboxy, carboxy(C.sub.1 -C.sub.6)alkyl, or a moiety of the formula: ##STR82## and, optionally 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6)alkyl, and (C.sub.1 -C.sub.6) alkoxy;
- wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl; and R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6) alkyl, (C.sub.4 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, a moiety of the formula: ##STR83## and a moiety of the formula:
- wherein m is an integer from 1-4; and
- R8 is selected from amino, amino(C.sub.1 -C.sub.6)alkyl and phenyl, benzyl, pyrrolidine, morpholine, and indole;
- and the pharmaceutically acceptable salts thereof.
4. A compound according to claim 3 wherein:
- X is oxygen,
- R.sub.2 is a moiety selected from those of the formulae: ##STR84## R.sub.6 and R.sub.7 are both hydrogen and R.sub.1, and n are as defined in claim 3.
12. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 1 in association with a pharmaceutically acceptable carrier.
13. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 2, in association with a pharmaceutically acceptable carrier.
14. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 3 in association with a pharmaceutically acceptable carrier.
15. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 4 in association with a pharmaceutically acceptable carrier.
16. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound selected from those of claim 3.
17. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound selected from those of claim 4.
5290814 | March 1, 1994 | Jackson et al. |
WO 9115495 | October 1991 | EPX |
- Mahan, M. J., J. M. Slauch, and J. J. Mekalanos, Science, 259, 686-688 (1993). S. Roychoudhury et al., Proc. Natl. Acad. Sci., 90, 965-969 (1993) Inhibitors of Two-component Signal Transduction Systems: Inhibition of Alginate Gene Activation in Pseudomonas Aeruginosa. International Search Report--International Application No. PCT/US96/10357--International Filing Date Jun. 18, 1996. Chem. Phar. Bull. (1982), 30(10), 3601-16, XP002024094 p.3611, Line 7-Line 13 (Sohda et. al.). J. Biol. Chem. (1992), 267(22), 15511-15, XP002024096, Huang, Jiamnin et al. Database WPI, Section Ch, Week 9631 Derwent Publications Ltd., London, GB; Class B03, AN 96-306532 XP002024098.
Type: Grant
Filed: Jun 2, 1995
Date of Patent: May 19, 1998
Assignee: Ortho Pharmaceutical Corporation (Raritan, NJ)
Inventors: Robert H. Chen (Belle Mead, NJ), Maud Urbanski (Belle Mead, NJ), Min Xiang (Bridgewater, NJ), John Francis Barrett (High Bridge, NJ)
Primary Examiner: Peter O'Sullivan
Attorney: Kenneth J. Dow
Application Number: 8/459,447
International Classification: A61K 31165; A61K 31135; A61K 3117; A61K 3119;